Rheumatoid Arthritis
Conditions
Keywords
Rheumatoid Arthritis, Denosumab, RANKL, RANK, AMG 162, joint damage, Developmental Phase III
Brief summary
To evaluate the inhibitory effect of progression, compared with placebo, in joint destruction by AMG 162 administered subcutaneously to rheumatoid arthritis participants.
Detailed description
To evaluate the inhibitory effect of progression, compared with placebo, in joint destruction by AMG 162 administered subcutaneously at a dose of 60 mg every 6 months or every 3 months for 12 months to rheumatoid arthritis participants.
Interventions
DRUGdenosumab
denosumab administered subcutaneously
DRUGplacebo
placebo administered subcutaneously to match denosumab
Sponsors
Daiichi Sankyo
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Diagnosed with rheumatoid arthritis according to the American College of Rheumatology (ACR) criteria for rheumatoid arthritis classification (1987 revision) or the 2010 ACR-EULAR (The European League Against Rheumatism) classification criteria for rheumatoid arthritis
Exclusion criteria
* Functional class IV according by the ACR revised classification (1991)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Total Sharp Score (TSS) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 12 | Change from baseline in Total Sharp Score (TSS) from baseline to month 12 was assessed. The TSS was defined as the sum of the erosion score and the joint space narrowing scores from radiographic assessments. The maximum radiographic TSS from the both hands/wrists and both feet is 448. Higher values represented greater damage. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Erosion Score From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 6 | Change from baseline in Erosion Score from baseline to month 6 was assessed. The Erosion Score was defined for the sum of the joint level erosion scores among the 44 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Erosion Score from both hands/wrist and both feet is 280. Higher values represented greater damage. |
| Change in Joint Space Narrowing From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 6 | Change from baseline in Joint Space Narrowing from baseline to month 6 was assessed. Joint Space Narrowing was defined for the sum of the joint level joint space narrowing scores among the 42 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Joint Space Narrowing from both hands/wrists and both feet is 168. Higher values represented greater damage. |
| Change in Total Sharp Score (TSS) From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 6 | Change from baseline in Total Sharp Score (TSS) from baseline to month 6 was assessed. The TSS was defined as the sum of the erosion score and the joint space narrowing scores from radiographic assessments. The maximum radiographic TSS from the both hands/wrists and both feet is 448. Higher values represented greater damage. |
| Change in Joint Space Narrowing From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 12 | Change from baseline in Joint Space Narrowing from baseline to month 12 was assessed. Joint Space Narrowing was defined for the sum of the joint level joint space narrowing scores among the 42 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Joint Space Narrowing from both hands/wrists and both feet is 168. Higher values represented greater damage. |
| Percent Change in Bone Mineral Density (BMD) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 12 | The percent change from baseline in Bone Mineral Density (BMD) to month 12 was assessed. Bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA). |
| Change in Erosion Score From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | baseline to month 12 | Change from baseline in Erosion Score from baseline to month 12 was assessed. The Erosion Score was defined for the sum of the joint level erosion scores among the 44 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Erosion Score from both hands/wrist and both feet is 280. Higher values represented greater damage. |
Countries
Japan
Participant flow
Recruitment details
A total of 679 participants who met all inclusion and none of the exclusion criteria were included in the study; efficacy outcomes were assessed in the Full Analysis Set (n=654).
Participants by arm
| Arm | Count |
|---|---|
| Denosumab 6 Months denosumab administered subcutaneously every 6 months
denosumab: denosumab administered subcutaneously | 217 |
| Denosumab 3 Months denosumab administered subcutaneously every 3 months
denosumab: denosumab administered subcutaneously | 219 |
| Placebo placebo administered subcutaneously to match denosumab
placebo: placebo administered subcutaneously to match denosumab | 218 |
| Total | 654 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 9 | 2 | 4 |
| Overall Study | Did not receive study drug | 6 | 3 | 3 |
| Overall Study | Disease progression | 0 | 3 | 0 |
| Overall Study | Invasive dental treatment | 3 | 5 | 6 |
| Overall Study | Other | 1 | 1 | 0 |
| Overall Study | Prohibited concomitant d | 1 | 5 | 0 |
| Overall Study | Protocol Violation | 2 | 1 | 3 |
| Overall Study | Withdrawal by Subject | 7 | 5 | 2 |
Baseline characteristics
| Characteristic | Denosumab 6 Months | Denosumab 3 Months | Placebo | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 77 Participants | 69 Participants | 55 Participants | 201 Participants |
| Age, Categorical Between 18 and 65 years | 140 Participants | 150 Participants | 163 Participants | 453 Participants |
| Age, Continuous | 58.1 years STANDARD_DEVIATION 12.3 | 58.2 years STANDARD_DEVIATION 12.04 | 55.8 years STANDARD_DEVIATION 11.7 | 57.4 years STANDARD_DEVIATION 12.04 |
| Body mass index (BMI) | 22.38 kg/m^2 STANDARD_DEVIATION 3.68 | 22.64 kg/m^2 STANDARD_DEVIATION 3.62 | 22.65 kg/m^2 STANDARD_DEVIATION 3.49 | 22.56 kg/m^2 STANDARD_DEVIATION 3.59 |
| Region of Enrollment Japan | 217 participants | 219 participants | 218 participants | 654 participants |
| Sex: Female, Male Female | 168 Participants | 154 Participants | 167 Participants | 489 Participants |
| Sex: Female, Male Male | 49 Participants | 65 Participants | 51 Participants | 165 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 221 | 1 / 222 | 0 / 224 |
| other Total, other adverse events | 127 / 221 | 122 / 222 | 125 / 224 |
| serious Total, serious adverse events | 19 / 221 | 19 / 222 | 13 / 224 |
Outcome results
Primary
Change in Total Sharp Score (TSS) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Total Sharp Score (TSS) from baseline to month 12 was assessed. The TSS was defined as the sum of the erosion score and the joint space narrowing scores from radiographic assessments. The maximum radiographic TSS from the both hands/wrists and both feet is 448. Higher values represented greater damage.
Time frame: baseline to month 12
Population: TSS was assessed in Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Total Sharp Score (TSS) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.99 score on a scale |
| Denosumab 3 Months | Change in Total Sharp Score (TSS) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.72 score on a scale |
| Placebo | Change in Total Sharp Score (TSS) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 1.49 score on a scale |
p-value: 0.0235van Elteren stratified rank test
Secondary
Change in Erosion Score From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Erosion Score from baseline to month 12 was assessed. The Erosion Score was defined for the sum of the joint level erosion scores among the 44 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Erosion Score from both hands/wrist and both feet is 280. Higher values represented greater damage.
Time frame: baseline to month 12
Population: The Erosion Score was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Erosion Score From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.51 score on a scale |
| Denosumab 3 Months | Change in Erosion Score From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.22 score on a scale |
| Placebo | Change in Erosion Score From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.98 score on a scale |
p-value: 0.0104van Elteren stratified rank test
Secondary
Change in Erosion Score From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Erosion Score from baseline to month 6 was assessed. The Erosion Score was defined for the sum of the joint level erosion scores among the 44 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Erosion Score from both hands/wrist and both feet is 280. Higher values represented greater damage.
Time frame: baseline to month 6
Population: The Erosion Score was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Erosion Score From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.34 score on a scale |
| Denosumab 3 Months | Change in Erosion Score From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.13 score on a scale |
| Placebo | Change in Erosion Score From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.58 score on a scale |
p-value: 0.1323van Elteren stratified rank test
Secondary
Change in Joint Space Narrowing From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Joint Space Narrowing from baseline to month 12 was assessed. Joint Space Narrowing was defined for the sum of the joint level joint space narrowing scores among the 42 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Joint Space Narrowing from both hands/wrists and both feet is 168. Higher values represented greater damage.
Time frame: baseline to month 12
Population: Joint Space Narrowing was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Joint Space Narrowing From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.48 score on a scale |
| Denosumab 3 Months | Change in Joint Space Narrowing From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.50 score on a scale |
| Placebo | Change in Joint Space Narrowing From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 0.51 score on a scale |
p-value: 0.257van Elteren stratified rank test
Secondary
Change in Joint Space Narrowing From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Joint Space Narrowing from baseline to month 6 was assessed. Joint Space Narrowing was defined for the sum of the joint level joint space narrowing scores among the 42 joints in both hands/wrist and both feet from radiographic assessments using the van der Heijde modified Sharp scoring method. The maximum radiographic Joint Space Narrowing from both hands/wrists and both feet is 168. Higher values represented greater damage.
Time frame: baseline to month 6
Population: Joint Space Narrowing was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Joint Space Narrowing From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.28 score on a scale |
| Denosumab 3 Months | Change in Joint Space Narrowing From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.35 score on a scale |
| Placebo | Change in Joint Space Narrowing From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.33 score on a scale |
p-value: 0.0448van Elteren stratified rank test
Secondary
Change in Total Sharp Score (TSS) From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo
Change from baseline in Total Sharp Score (TSS) from baseline to month 6 was assessed. The TSS was defined as the sum of the erosion score and the joint space narrowing scores from radiographic assessments. The maximum radiographic TSS from the both hands/wrists and both feet is 448. Higher values represented greater damage.
Time frame: baseline to month 6
Population: TSS was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Denosumab 6 Months | Change in Total Sharp Score (TSS) From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.62 score on a scale |
| Denosumab 3 Months | Change in Total Sharp Score (TSS) From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.48 score on a scale |
| Placebo | Change in Total Sharp Score (TSS) From Baseline to Month 6 Following Subcutaneous Administration of Denosumab or Placebo | 0.92 score on a scale |
p-value: 0.036van Elteren stratified rank test
Secondary
Percent Change in Bone Mineral Density (BMD) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo
The percent change from baseline in Bone Mineral Density (BMD) to month 12 was assessed. Bone mineral density (BMD) was measured by dual x-ray absorptiometry (DXA).
Time frame: baseline to month 12
Population: Bone mineral density was assessed in the Full Analysis Set.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Denosumab 6 Months | Percent Change in Bone Mineral Density (BMD) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 3.99 percent change | Standard Error 0.24 |
| Denosumab 3 Months | Percent Change in Bone Mineral Density (BMD) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | 4.88 percent change | Standard Error 0.24 |
| Placebo | Percent Change in Bone Mineral Density (BMD) From Baseline to Month 12 Following Subcutaneous Administration of Denosumab or Placebo | -1.03 percent change | Standard Error 0.25 |
p-value: <0.000195% CI: [4.41, 5.63]Regression, Cox